Haemophilus influenzae b is the most common cause of bacterial meningitis and other invasive infections in children in the United States. Extrapolating from prospective data gathered in Fresno County, Calif., approximately one in 300 newborns in the United States will develop bacteritic H. influenzae disease before the age of five years, and two-thirds of these episodes are associated with meningitis. Despite therapy with antibiotics, the mortality of Haemophilus meningitis remains at approximately 5%, and serious neurologic sequalae occur in as many as 10 to 25% of survivors. Since 1974, strains of Haemophilus resistant to ampicillin have emerged in the United States. By 1981 these strains were prevalent in nearly all communities, and b Haemophilus strains resistant to chloramphenicol or to multiple antibiotics have also been described. Recently, type b Haemophilus has been implicated as a cause of epidemic disease in children attending day care centers, a problem which appears to be increasing in direct proportion to the increase in the number of women entering the work force. These concerns have heightened interest in developing a vaccine for prevention of systemic Haemophilus infections in infants and young children.
Considerable data indicate that the type b capsule of Haemophilus influenzae, a heteropolymer of approximately equal amounts of ribitol, ribose and phosphate (PRP), is an important determinant of virulence, enabling the organism to resist host defenses. Antibodies directed at the type b capsule confer protection against disease by initiating opsonization and complement-dependent bacteriolysis. During the last three decades, considerable effort has been made to purify and characterize this capsular polysaccharide. A type b capsular polysaccharide vaccine was prepared which was immunogenic in adults and in children older than 18 months of age, but failed to elicit immunity in infants, the age group at greatest risk of Haemophilus disease. (Makela, P. M. et al., J. Infect. Dis. 136: S43; 1977).
The purified type b polysaccharide appears to act as a thymic-independent antigen. Booster immunization does not result in either a memory or an accelerated antibody response (Anderson, P. et al., J. Infect. Dis. 136, S57; 1977).
The carrier-hapten concept was established by Landsteiner in 1926, and a general method used to create a covalent link between PRP and a protein carrier was published by Schneerson et al. in 1980 (J. Exp. Med. 152, 361; 1980). In such a vaccine an antigenic, but weakly or non-immunogenic molecule, a hapten, contributes a new antigenic specificity to an immunogenic carrier molecule.